Many biological processes are carried out by populations of cells. For example, cells of the immune system are recruited from the bloodstream to areas of inflammation or infection, resulting in an accumulation of immune cells at the affected site. A marked infiltration of immune cells often occurs in tissues affected by autoimmune diseases, cancers and infections. Likewise, transplant rejection is mediated by host immune cells that enter and destroy the transplanted tissue. There is also growing evidence that stem cells originating in the bone marrow migrate through the bloodstream and assist in the regeneration of damaged tissues.
Furthermore, the most immediately promising area of biologic therapy involves the emerging field of cellular therapy. Cellular therapy is broadly defined as the treatment of human disease by the administration of therapeutic cells that have been selected, multiplied, and pharmacologically treated outside the body, or ex vivo. These cells may be derived from the patient (autologous cells), from another human (allogenic cells), from other organisms (xenogenic cells), or from immortalized cell lines.
Cells represent the ultimate therapeutic system because of their ability to carry out complex functions and their responsiveness to changes in the surrounding tissue or host organism. In the simplest mode of cellular therapy, cells can be isolated, grown in quantity ex vivo, and implanted in patients to produce and secrete soluble factors that directly address the mechanism of disease. Cells can also accomplish tasks as complex as reconstitution of tissues, organs, or immune responses based on their ability to home to specific sites within the body, to exit from circulation, and to integrate into specific tissue or differentiate into new tissue. Other cellular therapeutics can be programmed for tumor killing or treating metastases (e.g., immunotherapeutics).
Although dynamic cell populations play a key role in significant diseases, present technologies for monitoring the location and movement of cells in vivo are quite limited. Typically, cell movements are monitored only in “snap shots” obtained by histological analysis of tissue biopsies. However, the process of sampling a tissue often alters the behavior of cells, and only a limited number of biopsies can be obtained from a particular tissue or organ. Some progress has been made studying cell movements via in vitro assays and isolated tissues ex-vivo. Existing instruments for non-invasive analysis of living organisms are, at present, ill-suited for tracking living cells. Light-based imaging technologies, such as bioluminescence (e.g. luciferases) technologies, are often ineffective at visualizing deep structures because most mammalian tissues are optically opaque. Positron emission tomography (PET) techniques using radioactively-labeled probes are highly sensitive. However, PET instrumentation is often limited to a resolution of several millimeters and is unable to resolve fine details of tissues and organs. Furthermore, labeled cells cannot be detected for time periods that extend beyond a typical PET radioisotope half-life, and generally PET is not useful for longitudinal studies. In order to gain a fundamental understanding of cellular processes, new ways to visualize and quantify the population dynamics of specific cell types in vivo must be developed.
Magnetic resonance imaging (MRI) is a widely used clinical diagnostic tool because it is non-invasive, allows views into optically opaque subjects, and provides contrast among soft tissues at reasonably high spatial resolution. Conventional MRI focuses almost exclusively on visualizing anatomy and has no specificity for any particular cell type. The ‘probe’ used by conventional MRI is the ubiquitous proton (1H) in mobile water molecules. New classes of exogenous MRI probes or reagents are needed to facilitate cell-specific imaging in living subjects.